In uncomplicated diverticular disease, treatment is aimed at relieving symptoms. The aim of the present study was to evaluate the efficacy of mesalazine for symptomatic relief of uncomplicated diverticular disease of the colon. Two hundred sixty-eight consecutive eligible outpatients (122 male, 146 female; age, 66.1 years; range, 31-81 years) were enrolled in four treatment schedules in a randomized fashion: Group R1 (66 patients), rifaximin, 200 mg bid; Group R2 (69 patients), rifaximin, 400 mg bid; Group M1 (67 patients), mesalazine, 400 mg bid; and Group M2 (66 patients), mesalazine, 800 mg bid. Treatments were administered for 10 days every month for 12 months. Clinical evaluations were performed at admission and at 3-month intervals for 12 months considering 12 clinical variables (upper and lower abdominal pain/discomfort, tenesmus, diarrhea, abdominal tenderness, fever, bloating, general illness, nausea, emesis, dysuria, bleeding) graded as 0 = no symptoms, 1 = mild, 2 = moderate, and 3 = severe. The Global Symptomatic Score (GSS) was calculated using the sum of each symptom score. Two hundred forty-four patients completed the 12- month study; 24 were discontinued (14 treated with rifaximin and 10 treated with mesalazine) either as voluntary dropouts or because they developed side effects and/or complications. Group M2 demonstrated a lower frequency of many symptoms after 6 and 12 months of treatment; the mean GSS was significantly lower in Group M2 after 6 and 12 months of therapy by both intention-to-treat and per-protocol analyses. Patients treated with mesalazine (Groups M1+M2) had a lower GSS than subjects treated with rifaximin (Groups R1+R2) during the 12-month follow-up period. We conclude that cyclic administration of mesalazine is effective for symptomatic relief of uncomplicated diverticular disease of the colon. Some symptoms showed greater improvement with mesalazine, 800 mg bid, than with the other treatment schedules.